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Are we on the brink of Alzheimer’s disease breakthrough?

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To rephrase a well-known saying, you wait decades for an Alzheimer’s breakthrough to come along, and then two potential new drugs that could slow the progression of the disease are unveiled within months of each other.

This week American pharmaceutical company Eli Lilly reported its donanemab drug has shown positive results in a late-stage trial, slowing the progress of cognitive decline in patients with early symptomatic Alzheimer’s by 35%.

According to the Indianapolis headquartered firm, the experimental drug also resulted in 40% less decline in the ability of the 1,736 patients involved in the trial, to perform activities of daily living, such as managing finances, driving, engaging in hobbies, and conversing about current events.

Almost half (47%) of those on donanemab had no clinical progression of disease at one year compared with 29% on placebo (defined as no decline in the commonly-used Clinical Dementia Rating Scale Sum of Boxes score).

Furthermore, Eli Lilly said participants on donanemab experienced a 39% lower risk of progressing to the next stage of disease compared to placebo.

It wasn’t all good news. Two volunteers – and possibly a third – died as a result of swelling in the brain.

But the announcement has come less than six months after lecanemab hit the headlines as a game changer in the treatment of Alzheimer’s – the first new such drug for 20 years.

Like lecanemab – which was approved by the US Food and Drug Administration (FDA) in January this year – donanemab is an antibody similar to those the body makes to fight viruses.

But these two drugs have been engineered to clear a protein called beta-amyloid, which forms sticky plaques on the brain, leading to nerve cell death. It has been strongly implicated in Alzheimer’s disease.

Based on its own results, Eli Lilly has indicated it plans to file for approval for donanemab with the FDA within weeks.

With one in nine of the world’s population aged 65 and over currently living with Alzheimer’s, finding a cure has become the pot of gold for scientists.

Until now, existing drugs have only been able to treat Alzheimer’s symptoms, not the root cause of this harrowing disease which slowly erodes a person’s memories, comprehension, judgement, and eventually even their ability to function.

According to the UK-based Alzheimer’s Society, there are currently 141 drugs being tested in clinical trials for the treatment of the disease. Of these, 78% are intended to try and slow the progress of Alzheimer’s.

So does donanemab mark the “significant step forward for people with early symptomatic Alzheimer’s disease” that Eli Lilly believes?

Here some of the world’s leading Alzheimer’s experts share their views on this latest disease-modifying treatment.

Maria Carrillo, the American Alzheimer’s Association’s chief science officer:

“These are the strongest phase 3 data for an Alzheimer’s treatment to date. This further underscores the inflection point we are at for the Alzheimer’s field. The progress we’ve seen in this class of treatments, as well as the diversification of potential new therapies over the past few years, provides hope to those impacted by this devastating disease.”

She said she looked forward to additional data, and if consistent with what had already been announced regarding donanemab’s efficacy and safety, supported FDA approval.

Dr Jina Swartz, chief medical officer at Exciva, a clinical stage biopharmaceutical company focused on delivering an innovative treatment to address symptoms of Alzheimer’s patients, headquartered in Heidelberg, Germany:

“These results look very impressive, although the side effect profile in terms of high incidence of ARIA remains concerning (to me, both as a neurologist clinician and a drug developer).

“Certainly, Lilly’s Alzheimer’s disease donanemab TRAILBLAZER programmes, which take into account tau levels and the extent of tau dissemination in the cortex, are the best and most well thought out in the field. We have all been waiting for these results with anticipation.

“Certainly, it looks like the landscape for treating AD (with these amyloid monoclonal antibody amyloid-targeting therapies, including Eisai’s lecanumab) is on the cusp of changing clinical practice in this field.

“However, these therapies will not prevent disease progression ultimately, so ongoing work and development of symptomatic strategies to treat the neuropsychiatric disturbances of Alzheimer’s disease dementia is still of the utmost importance – to allow people to live well with Alzheimer’s disease dementia and maintain their quality of life and that of their family members and/or caregivers.

“In addition, it needs to be understood that these therapies are very expensive, require monthly infusions, regular MRI scans to monitor for AEs like ARIAs and the requirement to make a diagnosis of cortical amyloid (and tau) – using PET, which is prohibitively expensive.

“There are many parts of the world where the diagnostic and therapeutic requirements cannot be met, nor can the cost of the drugs be afforded. And even in the developed world (USA, Western Europe, parts of Asia-Pacific), patients will still require geographical access to a PET scanner and an infusion centre.

“So it will be interesting to see if/how this creates a significant disparity in access between the wealthy, developed nations (or even regions within a country)  and those parts of the world where this cannot be afforded.”

Dr Nick Fox, professor of neurology and group leader at the UK Dementia Research Institute, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust (UCLH):

“Although we only have a press release, this announcement is consistent with earlier phase 2 results – and confirms that we are in a new era of disease modification for Alzheimer’s disease. Dramatic and rapid amyloid removal was accompanied by slowing of cognitive decline.

“The challenge now is to be able to deliver these therapies in already stretched health care systems and to do so safely.”

Dr Richard Oakley, associate director of research at the UK-based Alzheimer’s Society:

“After 20 years with no new Alzheimer’s drugs, we now have two potential new drugs in just 12 months – and for the first time, drugs that seem to slow the progression of disease. This could be the beginning of the end of Alzheimer’s disease.

“While we’ve seen lecanemab could slow progression by over seven months, we’ll need to see the full results to know if donanemab could do the same or even better. We’re so proud that Alzheimer’s Society funded researchers discovered the role of amyloid in Alzheimer’s disease over 30 years ago which made today’s breakthrough possible.

“We need decisions as quickly as possible from the regulators MHRA and NICE. But that’s not the end of the story – we can’t end up in a situation where there are new drugs being approved but people can’t get access to them early in their dementia journey when they work best = we need more accurate, earlier dementia diagnosis in the NHS.”

Dr Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, launched in 1998 by co-chairmen Leonard A. Lauder and Ronald S. Lauder of the Estée Lauder Companies cosmetics family:

“This is very encouraging news for the millions of patients and families suffering from Alzheimer’s disease. These data are another proof point that amyloid-targeting drugs are a first step to slowing cognitive and functional decline, providing a clinically meaningful benefit to patients.

“Based on our understanding of the biology of aging, we know the accumulation of misfolded proteins is one pathway, among others, that contributes to the onset of Alzheimer’s. Our job now is to develop the next generation of drugs that can target all these pathways and be used in combination with one another for a precision medicine approach enabled by new biomarkers.

“While the results from this trial are highly significant, further progress is needed to achieve 100% slowing of cognitive decline.”

Dr Marc Busche, UK Dementia Research Institute group leader, University College London (UCL):

“This clinical trial is a real breakthrough, demonstrating a remarkable 35% slowing of cognitive decline in Alzheimer’s patients with high amyloid-beta but low tau burden. I believe this therapy has the potential to significantly improve patients’ and families’ lives today. Notably, the beneficial effect was smaller in those with high tau levels, suggesting a potential interaction between these pathogenic proteins.

“Looking ahead, I anticipate that concurrently targeting amyloid-beta and tau could lead to even better patient outcomes, making this a crucial focus for future research and the next generation of clinical trials.”

Dr Liz Coulthard, associate professor in Dementia Neurology at the University of Bristol, said:

“At face value, these data look positive, but we need to see the full dataset. Donanemab seems to help people with early Alzheimer’s retain cognitive function for longer – and this effect looks to be clinically meaningful. Donanemab might help people live well with Alzheimer’s for longer.  If approved alongside lecanemab, this potentially brings a choice of treatments for patients.

“The trial design means that we may be able to target the drug towards people who will benefit most.

“There are significant side effects, and we need to know more about how these have affected people.  We also need to know the longer-term effects of donanemab.”

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Ageing fight revealed in new ‘muscle map’

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The first comprehensive cell atlas of ageing human muscle reveals the intricate genetic and cellular processes behind muscle deterioration and mechanisms to counteract it.

How muscle changes with ageing, and tries to fight its effects, is now better understood at the cellular and molecular level with the first comprehensive atlas of ageing muscles in humans.

Researchers from the Wellcome Sanger Institute and their collaborators at Sun Yat-sen University, China applied single-cell technologies and advanced imaging to analyse human skeletal muscle samples from 17 individuals across the adult lifespan. By comparing the results, they shed new light on the many complex processes underlying age-related muscle changes.

The atlas uncovers new cell populations that may explain why some muscle fibres age faster than others. It also identifies compensatory mechanisms the muscles employ to combat ageing.

The findings offer avenues for future therapies and interventions to improve muscle health and quality of life as we age.

This study is part of the international Human Cell Atlas initiative to map every cell type in the human body, to transform understanding of health and disease.

As we age, our muscles progressively weaken. This can affect our ability to perform everyday activities like standing up and walking. For some people, muscle loss worsens, leading to falls, immobility, a loss of autonomy and a condition called sarcopenia. The reasons why our muscles weaken over time have remained poorly understood.

In this new study, scientists from the Wellcome Sanger Institute and Sun Yat-sen University, China used both single-cell and single-nucleus sequencing techniques along with advanced imaging to analyse human muscle samples from 17 individuals aged 20 to 75.

The team discovered that genes controlling ribosomes, responsible for producing proteins, were less active in muscle stem cells from aged samples. This impairs the cells’ ability to repair and regenerate muscle fibres as we age. Further, non-muscle cell populations within these skeletal muscle samples produced more of a pro-inflammatory molecule called CCL2, attracting immune cells to the muscle and exacerbating age-related muscle deterioration.

Age-related loss of a specific fast-twitch muscle fibre subtype, key for explosive muscle performance, was also observed. However, they discovered for the first time several compensatory mechanisms from the muscles appearing to make up for the loss. These included a shift in slow-twitch muscle fibres to express genes characteristic of the lost fast-twitch subtype, and increased regeneration of remaining fast-twitch fibre subtypes.

The team also identified specialised nuclei populations within the muscle fibres that help rebuild the connections between nerves and muscles that decline with age. Knockout experiments in lab-grown human muscle cells by the team confirmed the importance of these nuclei in maintaining muscle function.

Veronika Kedlian, first author of the study from the Wellcome Sanger Institute, said: “Our unbiased, multifaceted approach to studying muscle ageing, combining different types of sequencing, imaging and investigation reveals previously unknown cellular mechanisms of ageing and highlights areas for further study.”

Professor Hongbo Zhang, senior author of the study from Sun Yat-sen University, Guangzhou, China, said: “In China, the UK and other countries, we have ageing populations, but our understanding of the ageing process itself is limited. We now have a detailed view into how muscles strive to maintain function for as long as possible, despite the effects of ageing.”

Dr Sarah Teichmann, senior author of the study from the Wellcome Sanger Institute, and co-founder of the Human Cell Atlas, said: “Through the Human Cell Atlas, we are learning about the body in unprecedented detail, from the earliest stages of human development through to old age.With these new insights into healthy skeletal muscle ageing, researchers all over the world can now explore ways to combat inflammation, boost muscle regeneration, preserve nerve connectivity, and more. Discoveries from research like this have huge potential for developing therapeutic strategies that promote healthier ageing for future generations.”

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UK body calls for more ageing research backing

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The British Society for Research on Ageing (BSRA) is calling for more public backing in the UK for research to help people stay healthier for longer, as an alternative to charities that support research on diseases.

The greatest risk factor for disease is ageing, but we have very little charitable support for research into how to slow ageing, the organisation warns.

Many diseases such as cancers and heart disease tragically shorten lives far too early, or like Alzheimer’s and arthritis, destroy quality of life for patients and carers. There is understandably huge public charitable support for more research. However, the greatest risk factor for those diseases, and even infectious diseases like COVID, is ageing.

Yet in comparison there is currently very little support for research to understand how we can slow ageing to prevent disease. This approach may be more productive in the long term to fight disease. Furthermore, keeping people healthier for longer, or avoiding chronic diseases all together, would be the most favourable outcome.

The UK population is ageing fast, putting pressure on the NHS and the economy. Despite this pressing problem all around us, there is no accessible way for people to support research into ageing in the UK. The BSRA aims to change that.

With a very small budget and almost completely run by volunteers, the BSRA has successfully funded several small research projects but progress needs to be accelerated. More funding is needed because it takes years to see the effects of ageing, so studies are long. Also ageing affects individuals in different ways, meaning that large numbers of people must be studied to make firm conclusions.

Therefore, there is an urgency to get studies funded and the BSRA has decided to launch an ambitious fundraising campaign to boost research into ageing. Initially, the Society aims to fund a series of one year research projects at the Masters degree level at universities across the UK and with plans to raise much more in the future to support longer and more ambitious projects that will impact the lives of the general public.

Chair of the BSRA, Prof David Weinkove from Durham University, says “The time is now to really get behind research into the biology of ageing. We have fantastic researchers across the country, but they are held back by a lack of funding. Evidence-based research is needed to understand how we people can stay healthier for longer, and to then we must make that knowledge available to as many people as possible”.

Dr Jed Lye says “This is a great opportunity for the public to help, for corporations to contribute, or philanthropists wanting a large impact with a relatively small donation; every £20,000 we raise can fund an entire year of research into ageing and longevity, and gets a budding scientist their research qualification.”

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More action needed to prevent arthritis, say researchers

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MSU researchers have concluded that little is being done to address the prevalence of early knee osteoarthritis (OA) symptoms faced by patients after anterior cruciate ligament (ACL) reconstruction, calling for more action.

Scholars from Michigan State University’s Department of Kinesiology have published a new study in the Journal of Athletic Training in January showing these OA symptoms persist throughout the first year following surgery and need to be addressed with early intervention.

“We’re trying to change the narrative,” said Assistant Professor Matthew Harkey, who authored the study. “We see fairly young, active individuals experiencing extensive symptoms, but these symptoms are not interpreted by clinicians as something that may be related to osteoarthritis.

“Ignoring these symptoms might be setting them up to experience long term decline and function.”

ACL reconstruction is an arthroscopic surgical procedure that replaces torn anterior cruciate ligament in the knee with a graft. According to the National Institutes of Health, approximately 400,000 procedures are completed each year in the United States.

A 2017 study showed that approximately 14 million individuals in the United States alone suffer from symptomatic early knee OA.

The research team examined a data set of 82 individuals who underwent ACL reconstruction, each of whom completed a survey regarding their knee pain and symptoms following surgery. The results showed nearly one-in-four participants reported persistent early arthritis symptoms from 6 to 12 months after knee surgery.

In April 2024, Harkey will head to Austria and present similar research at the Osteoarthritis Research Society International Conference. This time, he used data from 3,200 individuals supplied by the New Zealand ACL Registry and found that close to one-in-three had early knee OA symptoms up to 24 months after ACL reconstruction.

The importance of intervention

Not addressing these symptoms in a timely manner places patients at risk for long-term structural decline, says Harkey. Although the study doesn’t show that patients experiencing symptoms will develop early OA, it heightens athletic trainers’ awareness of the possibility of symptoms, which could be addressed with intervention.

“It’s a bit complex – we can’t outright say arthritis is developing, but there’s a large group of patients whose symptoms linger long after surgery,” Harkey pointed out. “Often, clinicians assume that these post-operative symptoms will naturally improve as patients reengage with their usual activities. However, what we’re seeing suggests these symptoms persist and likely require a targeted approach to manage or improve them.”

According to Harkey, intervention could include exercise or physical therapy to help maintain strength and movement. He added that the healthcare infrastructure remains a barrier for patients, who often are limited to a low number of physical therapy visits through their healthcare plans.

The co-authors of the study with MSU affiliations include Ashley Triplett, assistant professor in the College of Education; Sheeba Joseph, associate professor, Colleges of Human and Osteopathic Medicine; Francesca Genoese, doctoral student in the Department of Kinesiology; Michael Shingles and Andrew Schorfhaar of Sparrow Hospital, alums of the College of Osteopathic Medicine.

Moving forward, Harkey aims to demonstrate how early knee OA after ACL reconstruction may lead to structural joint damage over time.

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